S210: AN OPEN-LABEL, GLOBAL, PHASE (PH) 1B/2 STUDY ADDING NAVTEMADLIN (NVTM) TO RUXOLITINIB (RUX) IN PATIENTS (PTS) WITH PRIMARY OR SECONDARY MYELOFIBROSIS (MF) WHO HAVE A SUBOPTIMAL RESPONSE TO RUX
Authors: John Mascarenhas, Tania Jain, Salman Otoukesh, Aaron T. Gerds, Alessandro Lucchesi, Iberia Romina Sosa, Kamel Laribi, Elena Mishchenko, Atanas Radinoff, Giulia Benevolo, Alessandro M. Vannucchi, Francoise Boyer, Philippe Quittet, Markus Radsak, Antoine Machet, Prithviraj Bose, Zhuying Huang, Hope Qamoos, Jesse Mcgreivy, Wayne P. Rothbaum, Srdan Verstovsek, Francesco Passamonti
Journal: HemaSphere (2023)

Topic: 16. Myeloproliferative neoplasms - Clinical Background: The majority of MF pts treated with approved Janus kinase inhibitors fail to achieve spleen volume response (SVR [³35%]) and continue to have persistent splenomegaly and MF-related symptoms. Nvtm is a potent, selective, orally available mouse double minute 2 inhibitor (MDM2i) that induces apoptosis in TP53 wild-type (TP53WT) CD34+ myeloblasts by overcoming dysregulated MDM2 (Lu 2017). Single agent nvtm demonstrated clinically meaningful and disease modifying activity in relapsed/refractory MF (Vachhani 2021; Al-Ali 2020). The combination of nvtm and rux leverages complementary mechanisms converging on the Bcl-2 family of proteins, suppressing pro-survival signaling adopted by tumor cells to evade cell death. Ex vivo testing of MF pt samples demonstrated that rux potentiates nvtm-driven p53-dependent killing of myeloblasts by inhibiting p21-controlled cell-cycle arrest and Bcl-xL, Bcl-2, and Mcl-1 escape pathways. Aims: To evaluate the safety, efficacy, and tolerability of nvtm added to rux in MF pts with suboptimal response to rux. Methods: This open-label, global Ph 1b/2 study (NCT04485260) enrolled adult pts with TP53WT MF with suboptimal response to rux. The Ph 1b 3 + 3 design evaluated 3 doses of nvtm added to a pre-study rux dose (≥18 weeks) to identify the recommended Ph 2 expansion dose (RP2D). Eligible pts must have been symptomatic with splenomegaly, ECOG 0-2, platelet count ³100×109/L, and on a stable rux dose (≥5 mg BID for ≥8 weeks). Pts with prior spleen response or progression on rux were excluded. Primary objectives were to determine RP2D (Ph 1) and SVR by central review at Week (Wk) 24 (Ph2). Key secondary objectives included Total Symptom Score (TSS) improvement ³50% by MFSAF v4.0 at Wk 24 (TSS-50). Results: As of 08 Feb 2023, median follow-up was 5.5+ months (mos) with 32 pts enrolled across 18 sites in seven countries. MF pts in this global study represent a heterogeneous group with poor disease control on rux monotherapy. In the Ph 1b portion, MF pts with suboptimal response on rux received nvtm at 120 mg (n=4), 180 mg (n=4), and 240 mg (n=6) added to their stable dose of rux. The RP2D was 240 mg QD (Day 1-7/28-day cycle). Preliminary results of the RP2D (n=24) are presented. The pre-study rux dose ranged from 5 to 25 mg BID. The median duration of prior rux treatment (tx) was 21.6 mos (7, 129), median spleen volume was 2111 cm3 (650, 3549), and median TSS was 15.2 (4, 49.1) (Table 1). At data cut, 11 pts crossed Wk 24, and five pts discontinued prior to Wk 24. By intent-to-treat (ITT) analysis (n=16), seven pts achieved SVR-25 (44%), five achieved SVR-35 (31%), and six achieved TSS-50 (38%) (Figures 1, 2). By modified ITT (Wk 24 pts only, n=11), 64% of pts achieved SVR-25, 45% achieved SVR-35, and 55% achieved TSS-50. The median decrease in circulating CD34+ cells from C1D1 pre-nvtm dose to combination Wk 12 or Wk 24 was -81%, -86%, respectively (n=6, n=3). Tx emergent-AEs (TEAEs), regardless of causality, were reported in 88% of pts, 33% grade (Gr) 3/4. The most common TEAEs were gastrointestinal and cytopenic. Gr 3/4 events occurred infrequently with no Gr 5 events reported on study (Table 1). Summary/Conclusion: Nvtm added to rux in MF pts with suboptimal response to rux provides clinically meaningful improvement in SVR and TSS at any stable rux dose with an acceptable safety profile. This data supports further investigation in a recently commenced Ph 3 study (BOREAS-2).Keywords: Apoptosis, Myelofibrosis, Ruxolitinib, TP53